The Function and Regulation of the GATA Factor ELT-2 in theC. elegansEndoderm

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Abstract

The GATA-type transcription factor ELT-2 is the major regulator of genes involved in differentiation, maintenance and function of the C. elegans intestine from the early embryo to the mature adult. The elt-2 gene responds to over-expression of the two GATA transcription factors END-1 and END-3 that specify the intestine, as well as to over-expression of the two GATA factors that are normally involved in intestinal differentiation, ELT-7 and ELT-2 itself. However, little is known about the molecular mechanisms that underlie these interactions, the general mechanisms by which ELT-2 levels are maintained throughout development, or how such systems respond to developmental perturbations. Here, we analyze regulation of the elt-2 gene through transgenic reporter assays, ELT-2 chromatin-immunoprecipitation and characterization of in vivo DNA-protein interactions. Our results lead to a model in which the elt-2 gene is controlled by three discrete regulatory regions conserved between C. elegans and C. briggsae and spanning >4 kb of 5'-flanking sequence. Although superficially the three regions are interchangeable, they have quantitatively different enhancer properties, and their combined activities indicate inter-region synergies. The regulatory activity of each region is mediated by a small number of conserved TGATAA sites that are also largely interchangeable and interact with different endodermal GATA factors with only modest differences in affinity. The redundant molecular mechanism that forms the elt-2 regulatory network is robust and flexible, as demonstrated by the fact that loss of the end-3 gene lowers ELT-2 levels by two-fold in the early embryo but ELT-2 returns to wildtype levels by hatching, several hours later. Finally, we report that when ELT-2 is expressed under the control of end-1 regulatory elements in addition to its own endogenous promoter, ELT-2 is able to replace the complete set of endoderm-specific GATA factors: END-1, END-3, ELT-7 (as well as the probably non-functional ELT-4). Thus, in addition to controlling gene expression during differentiation, ELT-2 is also capable of specifying the entire C. elegans endoderm.

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